The theme of this program project is identification of molecules which, upon interaction with cells of the immune system, mediate autoimmune diseases. Our goal is to identify interactions which can be blocked if they result in harmful responses, and augmented if they are protective. Six projects are proposed--3 in SLE; 1 each in collagen-induced arthritis, spondyloarthritis, and EAE. Two cores are proposed--1 for synthesis of peptides and the other for cell sorting and FACS analysis. Each of the 6 projects will use both cores. A total of 12 UCLA investigators will participate (7 PhD, 5 MD), aided by 2 outside consultants. Nine of the investigators are senior faculty; 9 have current NIH support. Project #1 (Tsao) examines the clinical and immune effects in normal mice of a transgene encoding a pathogenic IgG anti-DNA, and will establish the interactions between MHC, B and T cells that result in suppression or enhancement of gene expression and lupus nephritis. Project #2 (Hahn, Weisbart) will identify the peptides responsible for B cell-T cell interactive activation that upregulates production of pathogenic autoantibodies in patients with SLE. Project #3 (Klotz) looks at TCR diversity antigen specificity, and other functional aspects of autoreactive T cells from autoimmune NZB/NZW mice; and will compare clinical and immune effects, in autoimmune and normal mice, of expression of a transgene encoding an autoreactive T cell TCR. Project #4 (Brahn, Sercarz) will identify peptides that activate a) T cells that cause collagen-induced arthritis in rats, and b) T cells that protect against the arthritis in rats and mice. Project #5 (Yu) will examine molecules in HLA-B27 (mimicking molecules in arthritogenic Yersinia) that my bind LPS-like molecules and thus activate cells to release mediators of inflammation. Project #6 (Sercarz) will establish the exact amino acid sequences required to bind a) TcR and b) MHC on the self-antigen MBP, using chimeric peptides containing both amino acid sequences which are encephalitogenic in B10.PL mice. Flanking amino acids which hinder binding will also be identified. The purpose of these experiments is to identify interactions between cell surface molecules and self or external molecules that result in enhancement (or suppression) of immune responses directed against self. This information should be useful for designing strategies to modify undesirable autoimmune responses.